Proceedings of the National Academy of Sciences of the United States of AmericaOct 16, 2026

S-adenosyl-L-homocysteine may extend lifespan by activating a protective response through the YBT1 transporter

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Updated Oct 17, 2026

Abstract

Transient production of reactive oxygen species (ROS) triggered by S-adenosyl-L-homocysteine (SAH) extends the yeast chronological lifespan.

SAH may mimic partial inhibition of its hydrolase, influencing aging processes in yeast.
The dual role of ROS in aging appears to depend on the level of SAH hydrolase activity.
Ybt1, an ATP-binding cassette transporter, is identified as a key factor in the effects of SAH.
Ybt1 helps move SAM from the cytosol to the vacuole, potentially affecting longevity.
Overexpression of YBT1 is associated with extended chronological lifespan through pathways involving nutrient sensing and energy regulation.

Simplified

S-adenosyl-L-methionine (SAM) is a fundamental methyl donor; however, the physiological role of its byproduct and competitive inhibitor, S-adenosyl-L-homocysteine (SAH), remains unclear. Here, we show that transient reactive oxygen species (ROS) production triggered by SAH during the early logarithmic phase mimics partial SAH hydrolase inhibition, extending the yeast chronological lifespan (CLS) through a hormetic mechanism. This study reveals that the dual nature of ROS in aging is determined by the specific degree of SAH hydrolase activity. We identified the adenosine 5'-triphosphate-binding cassette (ABC) transporter Ybt1 as a key downstream effector of SAH. Ybt1 localizes to the vacuolar membrane and facilitates the sequestration of SAM from the cytosol into the vacuole. Notably, YBT1 overexpression extends CLS, mimicking SAH effects through an integrated pathway involving target of rapamycin complex 1 downregulation, autophagy, and adenosine 5'-monophosphate-activated protein kinase activation. Our findings establish that SAH acts as a metabolic signal coupling nutrient and energy availability to longevity via Ybt1, defining an adaptive/hormetic response for lifespan regulation in yeast.

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S-adenosyl-L-homocysteine may extend lifespan by activating a protective response through the YBT1 transporter

Abstract

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